Tuesday, May 20, 2008

My blood test says I don't have Lyme disease.

Unfortunately, many of the patients that I see have been worked up by other physicians and told they do not have Lyme disease. Usually the physician is unfamiliar with the symptoms of chronic Lyme disease and may have ordered a blood test at the urging of the patient. The blood test is negative, so the patient is told they don't have it. When doctors order the usual blood test for Lyme disease they get a test called an ELISA, which looks for antibodies against Borreliaburdorferi, the bacteria responsible for Lyme disease. Without going into the technical details, this test provides a color reaction when these antibodies are present and react with Lyme bacteria. The amount of color change is read by a device which provides a numerical index. If the index exceeds a predetermined threshold the test is read as positive. If it is less than the threshold the result is negative. When the index is in the positive range a second test called a Western Blot if performed to confirm the diagnosis. This test looks for specific antibodies against Lyme which settle out on a diffusion medium based on their weights. These individual antibody-antigen reactions are called bands. They are labeled based on their molecular weight in kilodaltons or their position on the medium. All of this gets quite technical, but it is necessary if I am to explain the issue.

When the test for Lyme was first developed it was found that many control sera (blood samples) from the control group of patients thought not to have Lyme showed a great deal of color change, indicating antibody reactions for Lyme. It is known that some antibodies are non specific and can react to a variety of foreign proteins. For example, some of the antibodies which react to the Lyme bacteria can also react to other germs which the individual may have been exposed to, including such viruses as Epstein Barr virus and Hepatitis C virus. It was believed by the early researchers that Lyme was a relatively rare disease; therefore, it was assumed that the widespread antibody reactivity in the control group was due to non-specific cross reactions to other germs the individuals may have been exposed to. A panel of experts was assembled to decide what the cut off point was to be for a positive test. This was a best guess based on information available at that time. The ELISA was supposed to be a screening test. Initially there was concern that this widespread cross reactivity might cause many false positive reports for Lyme disease. This test was meant to be sensitive, but not specific. This means that it was supposed to pick up all blood samples which tested positive for Lyme exposure but would also find false positives: individuals who did not have Lyme exposure but a nonspecific cross reaction.. A second tier test was put in place to make sure all the ELISA positives were truly positive. This is called the Western Blot.

There is a problem with all this. Although it sounds good in theory; it doesn't work. Most patients who test positive by the Western Blot, the more accurate test, are negative by the ELISA. This means the scientists who set the bar for positivity for the ELISA had made a critical error. They set the bar too high and were screening out many patients who in fact had been exposed to Lyme. Instead of providing some false positive results, the ELISA was providing false negative results. This is the exact opposite of what the test was supposed to do! It was incorrectly calibrated. It is hard to fathom, but most physicians, including infectious disease experts, fail to understand the significance of this point. The bottom line is that most patients who are told their Lyme test is negative have only had an ELISA test, a test which can be clearly shown to be inadequate and insensitive. What about the Western Blot? This is also an imperfect test.

The Western Blot (WB) identifies small proteins circulating in the blood called immunoglobulins. Specifically, two classes of immunoglobulins are tested. The are called IgM and IgG. All things being equal, IgM shows up early in infections and IgG shows up later later. There are 14 IgM bands and 14 IgG bands for a total of 28. Most labs only report 13 bands. What happened to the other 15? This goes back to 1994. The CDC (Center for Disease Control) created what is called a national surveillance criteria. These particular bands were chosen for epidemiological, research purposes. They were never studied for the purposes of creating a definitive diagnostic test. And there is another reason. The Lyme vaccine which was being developed at that time would cause reactions at some of the key bands, so they were omitted from the assay. Hold on. The vaccine has been off the market for many years. No one has ever bothered to add back these key markers to the lab assays! With the WB we are only getting half a loaf. The most important bands react with proteins on the outer surface of the Lyme bacteria called. These proteins are called outer surface proteins, or Osps. Three key Osps have been identified. OspA, OspB and OspC. The 13 test WB only looks for one of these three key antibodies directed against Lyme! It seems the standard WB performed by most labs is quite lacking.

Doctors who are better informed about these issues order WB Lyme tests at specialty labs such as IgeneX, and get all 28 bands: better, but not perfect. Even this test probably misses about 30% of the cases. Frequently, IgeneX will report results which are borderline and recommend further testing. Why does this happen?

Doctors who are familiar with chronic Lyme disease know that it suppresses the immune response. Over time, patients who are chronically infected have lower and lower antibody responses, which over time may disappear.This means that the sickest patients frequently have the most negative lab results. What to do?

It is a clinical diagnosis. Even the CDC says that lab reports cannot be relied upon. The physician actually has to reach into his black bag and pull out his stethoscope. A careful history and physical is the best way to make the diagnosis. There are other labs and radiographic tests which help as well. There are specific abnormalities on the physical exam which are very useful. The diagnosis can be tricky. It requires an understanding of the pathophysiology of the disease, the symptoms and all the diagnostic tests which add up to making the diagnosis. The diagnosis can be made reliably by a physician who is versed in many of its mysteries.As controversial as diagnosis is, treatment is a whole other can of worms.